Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278

Carson W Reed; Jordan P Washecheck; Marc C Quitlag; Matthew T Jenkins; Alice L Rodriguez; Darren W Engers; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley

doi:10.1016/j.bmcl.2019.03.016

Surveying heterocycles as amide bioisosteres within a series of mGlu₇ NAMs: Discovery of VU6019278

Bioorg Med Chem Lett. 2019 May 15;29(10):1211-1214. doi: 10.1016/j.bmcl.2019.03.016. Epub 2019 Mar 15.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁴ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: colleen.m.niswender@vanderbilt.edu.
⁵ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

PMID: 30910459
DOI: 10.1016/j.bmcl.2019.03.016

Abstract

This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu₇ negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu₇ NAM chemotype led to the discovery of VU6019278, a potent mGlu₇ NAM (IC₅₀ = 501 nM, 6.3% L-AP₄ Min) with favorable plasma protein binding (rat f_u = 0.10), low predicted hepatic clearance (rat CL_hep = 27.7 mL/min/kg) and high CNS penetration (rat K_p = 4.9, K_p,uu = 0.65).

Keywords: Metabotropic glutamate receptor; Negative allosteric modulator (NAM); Structure-activity relationship (SAR); VU6019278; mGlu(7).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Amides / chemistry*
Animals
Central Nervous System / metabolism
Hepatocytes / cytology
Hepatocytes / metabolism
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / metabolism
Inhibitory Concentration 50
Pyrazoles / chemistry
Pyrazoles / metabolism
Rats
Receptors, Metabotropic Glutamate / chemistry*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Amides
Heterocyclic Compounds
Pyrazoles
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor 7